Processes for the preparation of prostaglandin amides

ABSTRACT

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, 
     
       
         
         
             
             
         
       
         
         
           
             where in the formula the bonds marked with dotted lines may be single or double bonds, in the case of double bounds at positions 5,6 and 13,14 they may be in cis or in trans orientation, Q stands for a hydroxyl-group and Z stands for a hydroxyl- or oxo-group, R 1  and R 2  independently represent hydrogen atom or a straight or branched C 1-10  alkyl- or aralkyl-group, optionally substituted with —ONO 2  group, or an aralkyl- or aryl-group, which contains heteroatom, R 3  represents a straight or branched, saturated or unsaturated C 4-6  hydrocarbon group, or a C 4-10  alkylcycloalkyl- or cycloalkyl-group, or an optionally with alkyl group or halogen atom substituted phenyl-, C 7-10  alkylaryl- or hetaryl-group, Y represents (CH 2 ) n  group or O atom or S atom, and where n=0-3.

This application is a Divisional of copending application Ser. No.14/123,497, filed on Jan. 29, 2014, which was filed as PCT InternationalApplication No. PCT/HU2012/000045 on May 25, 2012, which claims thebenefit under 35 U.S.C. §119(a) to Patent Application No. P11 00291,filed in Hungary on Jun. 2, 2011 and Patent Application No. P11 00292,filed in Hungary on Jun. 2, 2011, all of which are hereby expresslyincorporated by reference into the present application.

The subject of the invention is a process for the preparation ofprostaglandin amides of the general formula (I).

In the compounds of the general formula (I)

the meanings of the substituents are as follows:the bonds marked with dotted lines may be single or double bonds, in thecase of double bounds in positions 5,6 and 13,14 they may be in cis orin trans orientation,Q represents hydroxy-group and Z represents hydroxy- or oxo-group,R¹ and R² independently represent hydrogen atom or a straight orbranched C₁₋₁₀ alkyl- or aralkyl-group, optionally substituted with—ONO₂ group, or an aralkyl- or aryl-group, which contains heteroatom,R³ represents a straight or branched, saturated or unsaturated C₄₋₆hydrocarbon group, or a C₄₋₁₀ alkylcycloalkyl- or cycloalkyl-group, oroptionally with alkyl group or halogen atom substituted phenyl-, C₇₋₁₀alkylaryl- or hetaryl-group,Y represents (CH₂)_(n) group or O atom or S atom, andn=0-3.

To prepare the prostaglandin amide derivatives economically, theappropriately substituted prostan acid has to be activated.

According to the present state of the art, carboxylic acids may beactivated by transformation into their

mixed anhydrides

activated esters or

activated amides,

and these compounds may then be further transformed into the desiredprostaglandin amide derivatives by reaction with the appropriate amines.

Of the above possibilities, activation of the chemically very sensitiveprostaglandin acids through ester formation is described for example inEP 0 660 716.

According to the process, the starting ester is formed with the help ofalkyl halogenides and the ester is then reacted with the appropriateamine to give the amide function.

Disadvantage of the method is that the use of alkyl halogenides at theend of a synthesis—in the last step—is to avoid, since alkyl halogenidesare proved to be genotoxic agents.

In addition, the resulting ester has to be treated with the appropriateamine at a high temperature for a long time and conversion rarelyexceeds 50% (EP0660716 page 42. Example 12). Considering the knowntemperature-sensitivity of prostaglandins, their treatment at hightemperature unfavourably influences the impurity profile and the yieldof the prostaglandin derivatives obtained in this way.

Preparation of the mixed anhydride and its reaction with theappropriately substituted amine is demonstrated in WO9153206.

Disadvantage of the method is that the active alkylating agents used forthe preparation of the mixed anhydrides—halogenated formic acid esters,pivaloyl chlorides and others—are proved to be genotoxic compounds.

In the method described in WO2005058812 (page 23) the startingcarboxylic acid is directly transformed into the ethyl amide by use ofthe activating agent 1-(3-dimethylaminopropyl)-3-carbodiimidehydrochloride (EDC HCl) and ethylamine. During the amidation reactionthe hydroxyl groups at positions 11 and 15 are protected withtetrahydropyran (THP) protecting group, which is then removed.

We have found that via the novel activated esters and novel activatedamides according to the invention, the compounds of the general formula(I) can be prepared under mild reaction conditions in high yield andpurity.

The compounds of the general formula (I) according to the invention canbe prepared by reacting an acid of the general formula (II),

where in the formulathe bonds marked with dotted lines may be single or double bonds, in thecase of double bounds at positions 5,6 and 13,14 they may be in cis orin trans orientation,Q represents hydroxy-group and Z represents hydroxy- or oxo-group,R³ represents a straight or branched, saturated or unsaturated C₄₋₆hydrocarbon group, or a C₄₋₁₀ alkylcycloalkyl- or cycloalkyl-group, oroptionally with alkyl group or halogen atom substituted phenyl-, C₇₋₁₀alkylaryl- or hetaryl-group,Y represents (CH₂)_(n) group or O atom or S atom, andn=0-3,

-   -   i.) with a compound suitable for the introduction of group R⁴,        where R⁴ represents

-   -   -   a group of formula a.),        -   and reacting the amide of the general formula (III), thus            obtained

-   -   -   where the meanings of Q, Z, R³, R⁴, Y and n are as defined            above, with an amine of the general formula (IV),            NHR¹R²  IV.        -   where the meanings of R¹ and R² are as defined above, or

    -   ii.) with a compound suitable for the introduction of group R⁵,        where R⁵ represents

-   -   -   a group of formula b.), c.), d.) or e.), where X stands for            halogen or hydrogen atom, and reacting the activated ester            of the general formula (V), thus obtained

-   -   -   where the meanings of Q, Z, R³, R⁵, Y and n are as defined            above, with an amine of the general formula (IV), where the            meanings of R¹ and R² are as defined above.

We have further found that the compounds of the general formula (I)according to the invention can also be prepared by reacting a compoundof the general formula (II) with a compound of the general formula(IV)—where in the formulae the meanings of the substituents are asdefined above—in the presence of 2-chloro-1,3-dimethylimidazoliniumchloride and a base (method iii.).

The intermediates of the general formula (III) and (V) are novelcompounds.

As for a compound suitable to introduce group R⁴, preferably1,1′-carbonyldiimidazole (DCI) or 1,1′-thiocarbonyldiimidazole, tointroduce group R⁵, in a given case in the presence of an activatingagent, N-hydroxysuccinimide, N-hydroxyphthalimide,N-hydroxy-5-norben-endo-2,3-dicarboxamide, 1-hydroxybenzotriazole,(benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate, N,N′-disuccinimidyl carbonate (DSC) orN,N′-disuccinimidyl oxalate, especially N,N′-disuccinimidyl carbonatemay be applied.

As for activating agent N,N′-diisopropylcarbodiimide,N,N′-dicyclohexylcarbodiimide or 2-chloro-1,3-dimethylimidazoliniumchloride, preferably N,N′-diisopropylcarbodiimide may be applied.

In the course of method i.) according to the invention, group R⁴ can beintroduced in an ether-type solvent or aromatic solvent or polar aproticsolvent or in their mixtures, using for example diisopropyl ether,tert-butyl methyl ether, 2-methyltetrahydofuran, toluene, anisole,dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, especiallytetrahydrofuran. The resulting activated amide of the general formula(III) is reacted with the amine of the general formula (IV) after orwithout isolation.

The reaction temperature during the introduction of group R⁴ is between20-80° C., preferably 70° C., while the reaction of the compounds offormula (III) and (IV) is carried out between 20-80° C., preferably atroom temperature.

In the course of method ii.) according to the invention, theintroduction of group R⁵ is carried out in an ether-type solvent or inan aromatic or polar aprotic solvent or in their mixtures, using forexample diisopropyl ether, tert-butyl methyl ether,2-methyltetrahydofuran, toluene, anisole, dimethylformamide,dimethylsulfoxide, N-methylpyrrolidone, especially tetrahydrofuran. Theresulting activated ester of the general formula (V) is reacted with theamine of the general formula (IV) after or without isolation. Thereaction temperature during the introduction of group R⁵ is between0-80° C., preferably at room temperature, while the reaction of thecompounds of formula (V) and (IV) is carried out between 20-80° C.,preferably at room temperature.

In the course of method iii.) according to the invention, the reactionis performed in an ether-type solvent or in an aromatic or polar aproticsolvent or in their mixtures, using for example diisopropyl ether,tert-butyl methyl ether, 2-methyltetrahydofuran, toluene, anisole,dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone ortetrahydrofuran. As for base, the usually applied bases, like pyridine,N-methylmorpholine, diisopropylethylamine,1,5-diazabicyclo[4,3,0]non-5-ene, 1,8-diazabicyclo[5,4,0]undec-7-ene ortriethylamine may be employed.

The reaction is carried out at a temperature between 0-70° C., in such away that to the solution of the compound of the general formula (II) inan organic solvent are added at 0-70° C., preferably at 30° C., thecompound of the general formula (IV), the2-chloro-1,3-dimethylimidazolinium chloride and 2 molar equivalentamount of the base. The mixture is first stirred at that temperature andthen gradually heated until the starting material disappears. Thereaction is followed by TLC.

Methods i., ii or iii may be carried out also under “one pot”conditions.

As for the amine of the general formula (IV) the amine appropriate forthe final compound, in the case of bimatoprost ethylamine may be used.

For the preparation of the compounds of the general formula (IA)

where in the formula the meanings of R¹, R², R³, Y and n are as definedabove,the compounds of the general formula (IIA) according to the inventionare used as starting materials.

The compounds of the general formula (IIA)

where in the formulaR³ represents a straight or branched, saturated or unsaturated C₄₋₆hydrocarbon group, or a C₄₋₁₀ alkylcycloalkyl- or cycloalkyl-group, oroptionally with alkyl group or halogen atom substituted phenyl-, C₇₋₁₀alkylaryl- or hetaryl-group,Y represents (CH₂)_(n) group or O atom or S atom, andn=0-3,may be prepared according to the invention by reducing the lactondiol ofthe general formula (XII),

where in the meanings of R³, Y and n are defined above, to thelactoltriol of the general formula (XIII),

where the meanings of R³, Y and n are defined above, the protectinggroup of the compound of formula (XIII) is then removed, and thecompound of the general formula (XIV), thus obtained,

where the meanings of R³, Y and n are defined above, is transformed byWittig reaction into the compound of the general formula (IIA).

Reduction of the compounds of the general formula (XII) may be carriedout by known methods, for example with diisobutylaluminium hydride intetrahydrofuran medium. The protecting group can be removed by knownmethods in acidic or alkaline medium, preferably in alkaline medium.

The lactoltriol derivatives of the general formula (XIII),

where R³ represents a straight or branched, saturated or unsaturatedC₄₋₆ hydrocarbon group, or a C₄₋₁₀ alkylcycloalkyl- or cycloalkyl-group,or optionally with alkyl group or halogen atom substituted phenyl-,C₇₋₁₀ alkylaryl- or hetaryl-group,Y represents (CH₂)_(n) group or O atom or S atom, and n=0-3,are novel compounds.

According to a further embodiment of the invention, the special compoundof the general formula IIA, where R³ stands for a phenyl group and Ystands for a —(CH₂)-group, compound of the formula (IIB) can be preparedalso in crystalline form.

The crystalline form of the compound of the formula (IIB) is new.

The compound of the formula (IIB) can be prepared in crystalline form,in such a way that to a mixture containing the compound of the formula(IIB) a mixture of ester type and ether type solvents is added.

According to the process dimethyl ether, diethyl ether, diisopropylether, preferably diethyl-ether and diisopropyl ether are used asether-type solvents, and ethyl-acetate, methyl-acetate,isopropyl-acetate, preferably isopropyl-acetate as ester-type solvents.The crystallisation is performed between (−)30° C. and 30° C.,preferably between 0-25° C. The suspension of crystals, thus obtained isstirred 1-24 hours, preferably 8 hours, then filtered and washed withether type solvent, preferably with diisopropyl ether. The filteredcrystals are dried under vacuum between 25-50° C., preferably at 35-40°C.

The compounds of the general formulae (II) and (XII) may be prepared byknown methods, for example as described in U.S. Pat. No. 5,359,095, WO93/00329.

The advantage of the method according to the invention is that thedesired bimatoprost final product—if desired—may be synthetized througha crystalline bimatoprost acid. Further advantage of the methodaccording to the invention is that the desired final product issynthetized through a novel intermediate, a crystalline, activated esteror amide, which—if desired—can be isolated and —if desired— can bepurified by crystallisation or chromatography. Due to the appliedcarboxylic acid activating agents (e.g. DSC, DCI), the protection of thesecondary hydroxyl groups in positions 9, 11 and 15 is not necessary,parallel reactions, for example dimer formation was not observed, eitherin the case of the activated ester or activated amide, or under theconditions of the final amide formation, and the activated carboxylicacid derivatives according to the invention were easily isolated withhigh yield and purity.

Surprisingly it was found that the crystalline activated carboxylic acidderivatives of the invention can be easily purified by crystallisationprocesses for eliminating the impurities and can also be transformedinto the desired amide final product simply, under mild reactionconditions and in high yield.

It is well known that in case of an active pharmaceutical ingredient(API) the level of the impurities is a key issue, in case of bimatoprostthe amount of every unknown impurity must be reduced under 0.1%.According to the process of the invention—to keep this very strictlimitation—the crystallisation of bimatoprost acid and thecrystallisation of the active carboxylic acid derivatives were usedinstead of the expensive preparative HPLC resolution described inWO09153206.

Further embodiment of our invention is a process for the preparation ofa high melting crystal form II of bimatoprost of the formula (IB).

By the process according to the invention a chemically andthermodynamically stable and from other crystal forms free, high meltingcrystal form II. of bimatoprost can be prepared.

The following patent applications deal with the crystallisation ofbimatoprost product: US 2005/0209337 A1, WO 2009/153206 A2, US2009/0163596 A1.

In Example 30 of US 2005/0209337 A1, the high melting point crystal formof bimatoprost (DSC peak read value 79° C.) (further on: crystal formII.) is characterized by its X-ray diffraction, by its IR spectrum inKBr pellet and by its DSC and TGA curves.

WO 2009/153206 describes the purification of bimatoprost product bypreparative HPLC, followed by crystallisation. Crystallisation iscarried out from acetonitrile solvent or from acetonitrile asdissolution and TBME (tert-butyl methyl ether) as precipitating solvent.According to the description, by that method the high melting pointcrystal form of bimatoprost (DSC peak read value 79° C.) can beprepared. By reproducing the method we did not succeed to obtain thehigh melting point crystal form of bimatoprost.

US 2009/0163596 discloses crystal form I. of bimatoprost and itspreparation. Crystal form I. of bimatoprost is characterized by itsmelting point (62-64° C.), by DSC, X-ray diffraction and IRinvestigation. It describes in details the crystallisation process, suchas the dissolution process (in an organic solvent or in the mixture ofan organic dissolution- and precipitation-solvent at a temperature nearthe boiling point), the cooling process, the separation of theprecipitated crystals from the mother liquor and the drying process (invacuum at low temperature). The high melting point crystal form (DSCpeak read value 79° C.) of bimatoprost cannot be prepared by the methodsdescribed in US 2009/0163596.

By the process of the invention the chemically and thermodynamicallystable, high melting point crystal form II. of bimatoprost (=highmelting point crystal form (DSC peak read value 79° C.)) can be preparedwhich is free of crystal form I. Form II. is characterized by itsmelting point (72-78° C.), by DSC investigation and by IR and X-raypowder diffraction studies.

The essence of the process is, that from a bimatoprost-containingreaction mixture after work-up and evaporation, or from any crystallineor non-crystalline form of bimatoprost or from their mixtures of anyratio, through crystallisation from a protic or ether-type solvent thethermodynamically stabile, pure form II. is prepared. Thecrystallisation process is the following: to the oily or crystallinecrude bimatoprost calculated amount of the solvent is added, then it isdried and periodically exposed to mechanical effect.

In accordance with the above, our invention relates to a process for thepreparation of form II. of bimatoprost of formula (IB), characterized inthat to a bimatoprost-containing reaction mixture after work-up andevaporation, or to any crystalline or non-crystalline form ofbimatoprost or to their mixtures of any ratio, calculated amount of anether-type or protic solvent is added, if desired the resulting mixtureis exposed to mechanical effect, then it is dried and homogenized.

The melting point of crystal form II. obtained in the above process isbetween 72-78° C., the endothermic peak, based on DSC investigation, isbetween 73-79° C. and the melting heat is higher than 75 J/g.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the IR spectrum of the lactoltriol of example 1a.

FIG. 2 shows the IR spectrum of the obtained Bimatoprost acid.

FIG. 3 presents the IR spectrum of crystal form I.

FIG. 4 presents the IR spectrum of crystal form II. obtained in theprocess according to the invention.

FIG. 5 presents the DSC curve of crystal form I.

FIG. 6 presents the DSC curve of crystal form II. obtained in theprocess according to the invention.

FIG. 7 presents the X-ray powder diffraction curve of crystal form I.

FIG. 8 presents the X-ray powder diffraction curve of crystal form II.obtained in the process according to the invention.

FIG. 9 shows the X-ray powder diffraction curve of the obtainedBimatoprost acid.

FIG. 10 shows the DSC curve of the obtained Bimatoprost acid.

FIG. 11A shows the MS spectrum for positive ionization of Example 5.

FIG. 11B shows the MSMS (precursor ion: 438.26) data of Example 5.

In the process according to the invention we use calculated amount,favourably 20-60 mass %, preferably 35 mass % amount of protic solvent,especially alcohols like methanol, ethanol and/or water. Preferablywater is used as protic solvent.

As mechanical effect we apply stirring or scratching, or both. The addedsolvent is removed by drying. Drying is performed at a temperaturebetween (−) 60° C. and 70° C., especially at 35° C., in vacuum.

As ether-type solvent we apply calculated amount, preferably 2000-8000mass % amount of dimethyl ether, diethyl ether, diisopropyl ether,preferably diethyl ether. The added solvent is removed by drying. Dryingis performed at low temperature, preferably between 0-(−)50° C. bypassing through nitrogen gas.

Identification of the products was carried out with the help of thefollowing analytical instruments:

NMR spectra were recorded by Bruker-Avance III-500 MHz instrument, DSCcurves by Mettler-Toledo DSC 1/700 instrument, IR spectra byPerkin-Elmer Spektrum 400 FT-IR spectrophotometer, MS spectra byShimadzu LC-MS-IT-TOF instrument. Melting points were determined by BUMMelting Point B-545 apparatus.

Further details of the invention are described in the examples, withoutto limit the invention to the examples.

EXAMPLES 1. Preparation of the Starting Material a.) Preparation of the[1,1′-Biphenyl]-4-carboxylic acid ((3aR,4R,5R,6aS)-hexahydro-4-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]-2-hydroxy-2H-cyclopenta[b]furan-5-yl)ester (PPB-lactoltriol)

The lacton group of 55 g of [1,1′-Biphenyl]-4-carboxylic acid((3aR,4R,5R,6aS)-hexahydro-4-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]-2-oxo-2H-cyclopenta[b]furan-5-yl)ester (PPB-lactondiol)

is reduced in 1000 ml of tetrahydrofuran (THF) solvent at (−)65-(−)85°C. with the hexane solution of 422 ml diisobutyl aluminium hydride(DIBAL-H). The reaction mixture is destroyed with NaHSO₄ solution, theaqueous phase is extracted with ethyl acetate, the organic phase iswashed with NaHCO₃ solution and the solvent is removed at 40-50° C. Thecrude material is evaporated to obtain 46.2 g oil.

Structural formula of the obtained PPB-lactoltriol:

From the crude oil after crystallization in tert-butyl methyl ether(TBME): hexane mixture, 41.6 g white crystals are obtained.

Melting point: 91.1-91.7° C.

IR spectrum of the lactoltriol of example 1a. is shown in FIG. 1.

¹³C and ¹H NMR data:

Number of the Position ¹³C (ppm) ¹H (ppm) protons Multiplicity Coupling(Hz) 6; OH 99.72; 100.64 5.57* (20H); 5.49 1 m J_(6,OH) = 4.65; 3.6 OH:6.05; 6.28 1 d 7 38.14; 38.44 2.57* (32H); 1.77 (39H) 1; 1 m; m 2.3-2.9;7.0; 1.78* (39H) J_(7α,7β) = 14.0 8 46.26; 45.69 2.57* (32H); 2.43 1 m—; J_(8,9) = 8.85-9.1 9 80.19; 80.92 4.60; 4.50 1 m J_(8,9) = 9.1;2.7-3.3; 7.3-7.4; J_(9,10) = 5.25 10 40.12**; 40.37** 1.98; 1.93; 1; 1m; m J_(9,10) = 5.5; 2.69; J_(10α,10β) = 13.6-13.65 11; OR 80.54; 79.035.12; 5.05 1 m 7.1-7.3 7.4-7.55; 9.8 12 54.12; 53.22 2.55* (33H); 3.11 1m —; 9.85-10.1; 7.55 13 129.38; 129.62 5.59* (19-20H); 5.59* (19-20H) 1m 6.3; J_(13,14) = 15.3 14 136.66; 136.69 5.65* (17-18H); 5.65* (17-18H)1 m J_(14,15) = 5.15; J_(13,14) = 15.45 15; OH 70.47; 70.39 3.98* (28H);3.98* (28H) 1 m J_(14,15) = 5.2-5.5 OH: 4.80* (24H); 4.79* (25H) 1 dJ_(15,OH) = 4.7; 4.8 16 40.09** 1.71-1.61* (40H) 1; 1 m; m 17 31.86;31.80 2.57* (32H); 2.55* (33H) 2 m 18 143.14 — — — — 19, 19′ 129.067.10; 7.06 1 d J_(19,20) = 7.3; 7.2 20, 20′ 129.09 7.23* (9H); 7.20*(10H) 1 t J_(19,20) = J_(20,21) = 7.4; 7.5 21 126.41; 126.37 7.14*(11H); 7.13* (12H) 1 t J_(20,21) = 7.3-7.45 22 166.07; 166.16 — — — — 23129.52; 129.48 — — — — 24, 24′ 130.71 8.04* (2H); 8.06* (1H) 1 dJ_(24,25) = 8.3; 8.4 25, 25′ 127.86 7.83* (3H); 7.81* (4H) 1 d J_(24,25)= 8.5; 8.4 26 145.64 — — — — 27 139.77 — — — — 28, 28′ 127.90 7.75*(5H); 7.73* (6H) 1 d J_(28,29) = 7.6; 7.95 29, 29′ 130.01 7.55 1 tJ_(28,29) = J_(29,30) = 7.4-7.8 30 129.33 7.47 1 t J_(29,30) = 7.3-7.35*Overlapping ¹H NMR signals (The number in brackets signifies theposition number of the signal group in the PMR spectrum, direction:towards decreasing shifts) **¹³C NMR signals overlapping with themultiplett of the DMSO solvent.

b.) Preparation of the(3aR,4R,5R,6aS)-hexahydro-4-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]-2H-cyclopenta[b]furan-2,5-diol,(lactoltriol)

46.2 g of [1,1′-Biphenyl]-4-carboxylic acid((3aR,4R,5R,6aS)-hexahydro-4-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]-2-hydroxy-2H-cyclopenta[b]furan-5-yl)ester (PPB-lactoltriol) oil is dissolved in 230 ml of methanol and afteradding 6.6 g of K₂CO₃ it is desacylated at 35-45° C. The pH of thereaction mixture is adjusted to 7-8 at (−)5-0° C. with 0.5 M phosphoricacid solution. The precipitated crystals are filtered off and washedwith methanol:water mixture. The mother liquor is evaporated, extractedwith ethyl acetate, the organic phase is dried over Na₂SO₄, the dryingmaterial is filtered off and the product is crystallized by the additionof hexane. 26 g of white crystalline material is obtained.

Structural Formula of the Product:

Melting point: 98-103° C.

¹³C and ¹H NMR data:

Number of the Position ¹³C (ppm) ¹H (ppm) protons Multiplicity Coupling(Hz) 6; OH 99.65; 100.48 5.46* (8H); 5.40 1 m J_(6,OH) = 4.65; 3.8 OH:5.92; 6.13 1 d 7 39.94; 38.77 1.81* (26H) 1; 1 m; m 1.97* (25H); 1.66*(27H) 8 45.63; 45.81 2.29* (22H); 2.22* (24H) 1 m 9 79.20; 80.97 4.38;4.32 1 m J_(9,10a) = 6.9; 7.3-7.55 10 41.53; 43.795 2.27* (23H); 1.48 1;1 m; m J_(9,10a) = 6.4-6.8; 7.1-7.4 2.30* (22H); 1.76* (27H) 11; OH77.62; 77.06 3.70; 3.61 1 m J_(11,OH) = 5.95; 5.85 OH: 4.75; 4.80 1 d 1256.80; 55.86 1.97* (25H); 2.53* (21H) 1 m 13 131.46; 132.11 5.54* (6H);5.54* (6H) 1 m J_(13,14) = 15.3 14 135.39; 135.16 5.49* (7H); 5.49* (7H)1 m J_(13,14) = 16 15; OH 71.14; 71.22 3.94* (16H); 3.94* (16H) 1 mJ_(15,OH) = 4.75; 4.35 OH: 4.72* (12H); 4.71* 1 d (13H) 16 40.26 1.74*(27H); 1.66* (27H) 1; 1 m; m 17 32.24; 32.27 2.63* (20H); 2.63* (20H) 1;1 m 18 143.23 — — — — 21* 129.20 7.22* (2H) 1 d J_(21,22) = 7.3 22*129.18 7.30 1 t J_(21,22) = J_(22,23) = 7.4-7.6 23* 126.48 7.19* (3H) 1t J_(22,23) = J_(23,24) = 7.25 24* 129.18 7.30 1 t J_(23,24) = J_(24,25)= 7.4-7.6 25* 129.20 7.22* (2H) 1 d J_(24,25) = 7.3 *Overlapping ¹H NMRsignals. (The number in brackets signifies the position number of thesignal group in the PMR spectrum, direction: towards decreasing shifts).

c.) Preparation of the7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-penten-1-yl]-cyclopentyl]-5-heptenicacid, (5Z)-(bimatoprost acid)

c1.) 108 g of 4-carboxybutylphosphonium bromide (KBFBr) is dissolved in800 ml of THF and the solution is cooled to 0-(−5)° C. To this solutionfirst 91 g of potassium tert-butylate (KOtBu), and then after stirringand cooling to (−10)-(−15)° C., the solution of 25 g of lactoltriol inTHF are added. When the expected conversion is reached the reactionmixture is destroyed with water, then EtOAc is added. The aqueous phaseis washed with EtOAc. The aqueous layer is acidified with NaHSO₄solution to pH=2 and extracted with EtOAc. The united organic phase iswashed with 15% NaCl solution, dried over Na₂SO₄, filtered andevaporated. The residue is crystallized from the mixture of ethylacetate and diisopropyl ether. The crystals are filtered off and washed,the filtrate solution is evaporated. The resulting yellow oil ispurified by chromatography on silica gel using diisopropyl ether-acetoneeluent. 25.5 g oil is obtained.

IR spectrum of the obtained Bimatoprost acid is shown in FIG. 2.

c2.) The product obtained in example 1/c1.) is dissolved in 60 ml ofisopropyl-acetate and under stirring 40 ml of diethyl-ether is added toit. Small amount of bimatoprost acid seeding crystal is added to thereaction mixture. Under stirring gradually cooled to 0° C. about 60 mlof diisopropyl-ether is added to it. The suspension is stirred at thistemperature for a night thereafter it is filtered and washed withdiisopropyl-ether and dried under vacuum. 20.4 g crystalline bimatoprostacid is obtained.

DSC curve of the obtained Bimatoprost acid is shown in FIG. 10 and X-raypowder diffraction curve in FIG. 9.

Structural Formula of the Product:

Melting point: 63.0-65.5° C.

¹³C and ¹H NMR data:

Number of the Position ¹³C (ppm) ¹H (ppm) protons Multiplicity Coupling(Hz) 1; COOH 175.30 —; COON: 12.02 —; COOH: 1 —; COOH: broad 2 34.102.23* (21H); 2.16* (22H) 1; 1 m; m 3 25.45 1.54* (26H) 2 m 4 27.09 2.01*(24H) 2 m J_(4,5) = 6.8-7.0 5 129.53 5.29 1 td J_(4,5) = 7.2 J_(5,6) =10.8 6 130.64 5.50* (7H) 1 td J_(6,7) = 7.8 J_(5,6) = 10.6 7 25.74 2.15*(22H); 2.04* (24H) 1; 1 m; m 8 49.81 1.34 1 m J_(8,9) = 5.75 9; OH 70.473.95* (13H); OH: 4.40 1 m; broad J_(8,9) = 5.75 10 44.89 2.24* (21H);1.48* (26H) 1; 1 m; ddd J_(10α,10β) = 14.1; 5.65-5.85; 2.3-2.4 11; OH76.69 3.71; OH: 4.55 1; OH: 1 m (ddd); broad J_(11,12) = 7.5 12 55.222.19* (21H) 1 m 13 133.05 5.40* (7H) 1 dd J_(12,13) = 7.7-8.15;J_(13,14) = 15.45 14 136.09 5.47* (7H) 1 dd J_(14,15) = 6.2-6.35;J_(13,14) = 15.4 15; OH 71.53 3.94* (13H); OH: 4.71 1; OH: 1 m; broadJ_(14,15) = 6.4 16 40.45* 1.75* (25H); 1.69* (25H) 1; 1 m; m 17 32.292.64 2 m 18 143.24 — — — — 19* 129.15 7.21* (5H) 1 d J_(19,20) = 6.9 20*129.20 7.30 1 t J_(19,20) = J_(20,21) = 7.5-7.55 21* 126.51 7.19* (5H) 1t J_(20,21) = J_(21,22) = 6.7-7.3 22* 129.20 7.30 1 t J_(21,22) =J_(22,23) = 7.5-7.55 23* 129.15 7.21* (5H) 1 d J_(22,23) = 6.9 *Partlyor fully overlapping ¹H NMR signals. (The number in brackets signifiesthe position number of the signal group in the PMR spectrum, direction:towards decreasing shifts).

2. Preparation of7-[3,5-Dihydroxy-2-(3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-5-heptenoicacid (2,5-dioxo-pyrrolidin-1-yl) ester (activated ester)

27.5 g of bimatoprost acid of example 1/c2.) is dissolved in 270 ml ofTHF and to it are added at room temperature 13.7 g ofN,N′-diisopropylcarbodiimide followed by 13.7 g of N-hydroxysuccinimide.The mixture is stirred at that temperature and then poured onto themixture of 1N NaHSO₄ solution and tert-butyl methyl ether (TBME). Thephases are separated. The organic phase is washed with 1N NaHCO₃solution, the aqueous-alkaline phase is extracted with TBME. The unitedorganic phase is dried over Na₂SO₄, filtered and evaporated. The residueis crystallized from hexane:acetone mixture to obtain 30.04 g whitecrystalline material.

Product:

Melting point: 93.5-103.4° C.

3

27.5 g of bimatoprost acid of example 1/c1.) is dissolved in 270 ml ofTHF and to this solution are added at room temperature 11.5 g ofpotassium carbonate and 19.6 g of N,N′-disuccinimidyl carbonate. Thereaction mixture is under stirring gradually heated to 60° C. and thenpoured onto the mixture of 1N NaHSO₄ solution and tert-butyl methylether (TBME). The phases are separated, the organic phase is washed with1N NaHCO₃ solution and the aqueous-alkaline phase is extracted withTBME. The united organic phase is dried over Na₂SO₄, filtered andevaporated. The residue is crystallized from hexane:acetone mixture toobtain 30.9 g white crystalline material.

Product:

Melting point: 93.5-103.4° C.

¹³C and ¹H NMR data:

Coupling constant (Hz) Numbering ¹³C (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz) 1 168.80 — — — 2 29.70 2.55** 2 t J_(2,3) = 7.43 24.29 1.61*** 2 m (tt) J_(3,4) = 7.4 4 25.70 2.06 2 m J_(4,5) = 7.2 5127.87 5.28 1 dt J_(5,6) = 10.7 6 130.27 5.48⁺ 1 dt (ddd) J_(6,7) = 7.47 24.83 7a: 2.14⁺⁺ 1 m 7b: 2.00 1 m 8 48.78 1.32 1 m (dddd) 10.4; 10.4;5.1; 5.1 9 69.53 3.915⁺⁺⁺ 1 m 9-OH 4.35 1 d J_(9,OH) = 5.0 10 43.94 β:2.20⁺⁺ 1 m(ddd) J_(gem) = 14.1; 8.2; 5.9 α: 1.44 1 ddd 5.6; 2.3 11 75.373.68 1 m (dddd) ~7.9; ~7.9; ~5.8; ~5.8 11-OH 4.50 1 d J_(11,OH) = 5.8 1254.22 2.16⁺⁺ 1 m 7.8; 3.8 13 132.02 5.37 1 dd J_(13,14) = 15.4;J_(12,13) = 8.1 14 135.16 5.44⁺ 1 m (dd) J_(14,15) = 6.3 15 70.563.909⁺⁺⁺ 1 m 15-OH 4.65 1 d J_(15,OH) = 4.7 16 39.49* 1.71*** 1 m1.65*** 1 m 17 31.35 2.60** 2 m 18 142.31 — — — 19, 23 128.19/128.247.17^(#) 2 d J_(19,20) = 7.4 20, 22 128.24/128.19 7.26 2 t J_(20,21) =7.4 21 125.55 7.15^(#) 1 t 24, 27 170.18 — — — 25, 26 25.42 2.80 4 s*Overlapped ¹³C NMR by the DMSO signal. **,***,⁺,⁺⁺,⁺⁺⁺,^(#)Overlapped¹H NMR signals.

4.) Preparation of7-[3,5-Dihydroxy-2-(3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-5-heptenoicacid 1,3-dioxo-1,3-dihydro-isoindol-2-yl ester (activated ester)

2 g of bimatoprost acid is dissolved in 20 ml of THF and to thissolution are added at room temperature 1 g of N-hydroxy-phtalimide and 1ml of N,N′-diisopropylcarbodiimide. The reaction mixture is stirred for2 hours and then poured onto the mixture of 1N NaHSO₄ solution andtert-butyl methyl ether (TBME). The phases are separated, the organicphase is washed with 1N NaHCO₃ solution and the aqueous-alkaline phaseis extracted with TBME. The united organic phase is dried over Na₂SO₄,filtered and evaporated. The residue is crystallized from hexane:acetonemixture to obtain 1.5 g white crystalline material.

Product:

Melting point: 83.2-84.5° C.

¹³C and ¹H NMR data:

Coupling constant (Hz) Numbering ¹³C (ppm) ¹H (ppm) Number of ¹HMultiplicity (+/−0.2 Hz) 1 169.82 — — — 2 29.63 2.64 2 t J_(2,3) = 7.4 324.29 1.65* 2 m (tt) J_(3,4) = 7.4 4 25.71 2.09 2 m J_(4,5) = 7.2 5127.84 5.30 1 dt J_(5,6) = 10.5 6 130.33 5.50 1 dt (ddd) J_(6,7) = 7.5 724.83 a: 2.16** 1 m J_(gem) = 12.6 b: 2.01 1 m (ddd) 8 48.79 1.325 1 m(dddd/tt) 10.7, 10.0; 5.3; 4.7 9 69.52 3.92*** 1 m 9-OH 4.38 1 dJ_(9,OH) = 4.9 10 43.95 β: 2.205** 1 m(ddd) J_(gem) = 14.1; J_(10β) =8.4 and 6.0 α: 1.44 1 ddd J_(10α) = 5.6 and 2.1 11 75.74 3.68 1 m(dddd/tt) ~7.8; ~7.8; ~6.0; ~6.0 11-OH 4.52 1 d J_(11,OH) = 5.8 12 54.232.165** 1 m 13 132.08 5.37 1 dd J_(13,14) = 15.4; J_(12,13) = 8.3 14135.18 5.44 1 m (dd) J_(14,15) = 6.4 15 70.56 3.89*** 1 m 15-OH 4.66 1 dJ_(15,OH) = 4.6 16 39.47^($) a: 1.69* 1 m b: 1.64* 1 m 17 31.34 2.58** 2m (td) 10.1 and 6.3 18 142.28 — — — 19, 23 128.16^($)/128.20 7.15⁺ 2 dJ_(19,20) = 7.5 20, 22 128.20/128.16^($) 7.24 2 t J_(20,21) = 7.3 21125.52 7.13⁺ 1 t 24, 31 161.81 — — — 25, 30 ~128.1^($) — — — 26, 29123.97 7.97⁺⁺ 2 m 27, 30 135.51 7.94⁺⁺ 2 m ^($)Overlapped ¹³C NMR by theDMSO signal. ^($$)Overlapped ¹³C NMR signals. *,**,***,⁺,⁺⁺Overlapped ¹HNMR signals.

5.) Preparation of7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-cyclopentyl]-N-ethyl-5-heptenamide,(5Z(−)bimatoprost) through the activated ester

27.5 g of bimatoprost acid is dissolved in 270 ml of THF and to thesolution are added at room temperature 13.7 gN,N′-diisopropylcarbodiimide and then 13.7 g of N-hydroxysuccinimide.The mixture is stirred at room temperature. The resulting activatedester is not isolated.

After the completion of the ester formation 70 ml of 2M ethylamine inTHF solution is added to the reaction mixture. The mixture is stirreduntil the expected conversion is reached, then it is poured onto themixture of 1N NaHSO₄ solution and tert-butyl methyl ether (TBME). Thephases are separated, the organic phase is washed with 1N NaHCO₃solution and the aqueous-alkaline phase is extracted with TBME. Theunited organic phase is dried over Na₂SO₄, filtered and evaporated toobtain 25.4 g of oil.

Product:

¹³C and ¹H NMR data:

Number of Coupling (Hz) Position ¹³C (ppm) ¹H (ppm) the protonsMultiplicity (+/−0.2 Hz) 1 172.51 — — — 2 35.88 2.02** 2 t J_(2,3) = 7.53 26.27 1.53*** 2 m (tt) J_(3,4) = 7.5 4 27.25 1.99** 2 m J_(4,5) = 7.25 129.78 5.30 1 dt J_(5,6) = 10.5 6 130.38 5.48⁺ 1 Dt (ddd) 7 25.722.15⁺⁺ 1 m 2.03** 1 m 8 49.78 1.35 1 m (dddd) 10.6; 10.6; 4.7; 4.7 970.45 3.95⁺⁺⁺ 1 m 9-OH 4.40 1 d J_(9,OH) = 4.9 10 44.85 β: 2.23⁺⁺ 1 m α:1.48*** 1 ddd J_(gem) = 14.2; 5.5; 2.2 11 76.67 3.71 1 m (dddd) ~7.5;~7.5; ~7.5; 6.5 11-OH 4.54 1 d J_(11,OH) = 5.8 12 55.15 2.19⁺⁺ 1 m 13132.91 5.41 1 dd J_(13,14) = 15.4; J_(12,13) = 8.0 14 136.00 5.47⁺ 1 M(dd) 15 71.41 3.94⁺⁺⁺ 1 m 15-OH 4.71 1 d J_(15,OH) = 4.6 16 40.36*1.74^(#) 1 m 1.70^(#) 1 m 17 32.25 2.61 1 m 2.675 1 m 18 143.21 — — —19, 23 129.13 7.21^(##) 2 d J_(19,20) = 7.4 20, 22 129.15 7.30 2 tJ_(20,21) = 7.4 21 126.46 7.19^(##) 1 t 24 (NH) 7.72 1 broad, tJ_(24,25) = 5.5 25 34.13 3.07 2 qd J_(25,26) = 7.2 26 15.70 1.02 3 t

The MS spectrum for positive ionization is shown in FIG. 11A.

Expected formula:

C₂₅H₃₇NO₄

Measured exact mass: 438.2648 [M+Na]+

Expected exact mass: 438.2615 [M+Na]+ ΔM=3.3 mDa and 7.53 ppm

C₂₅H₃₅NO₃ (M-H₂O)

Measured exact mass: 398.2655 [M-H₂O+H]+

Expected exact mass: 398.2690 [M-H₂O+H]+ ΔM=−3.5 mDa and 8.79 ppm

The MSMS (precursor ion: 438.26) data is shown in FIG. 11B.

Expected formula:

C₂₅H₃₅NO₃ (M-H₂O)

Measured exact mass: 420.2520 [M-H2O+Na]+

Expected exact mass: 420.2509 [M-H2O+Na]+ ΔM=1.1 mDa and 2.62 ppm

C₂₅H₃₂NO₃ (M-H₂O-5H)

Measured exact mass: 394.2366 [M-H₂O-5H]+

Expected exact mass: 394.2377 [M-H₂O-5H]+ ΔM=−1.1 mDa and 2.79 ppm

C₂₅H₃₀NO₂ (M-2×H₂O-5H)

Measured exact mass: 376.2258 [M-2×H₂O-5H]+

Expected exact mass: 376.2271 [M-2×H₂O-5H]+ ΔM=−1.3 mDa and 3.46 ppm

6.) Preparation of Bimatoprost Through the Activated Ester

27.5 g of bimatoprost acid is dissolved in 270 ml of THF and to thissolution are added at room temperature 11.5 g of potassium carbonate and19.6 g of N,N′-disuccinimidyl carbonate. The reaction mixture isgradually heated to 60° C. under stirring. The resulting activated esteris not isolated.

After the formation of the activated ester, 70 ml of 2M ethylamine inTHF solution is added to the reaction mixture. When the reaction iscompleted the mixture is poured onto the mixture of 1N NaHSO₄ solutionand EtOAc. The organic phase is washed with 1N NaHCO₃ solution, theaqueous-alkaline phase is extracted with EtOAc. The united organic phaseis washed with NaCl solution and dried over Na₂SO₄. The drying materialis filtered off, the filtrate is evaporated to obtain 25.7 g of oil.

Product:

7.) Preparation of Bimatoprost Through the Activated Amide

27.5 g bimatoprost acid is dissolved in 270 ml of pyridine and 13.7 g of1,1′-carbonyldiimidazole is added to it. The mixture is stirred at20-25° C. until the activated amide formation takes place. The resultingactivated amide is not isolated.

70 ml of 2M ethylamine in THF solution is added to the reaction mixtureat room temperature and the mixture is stirred until the expectedconversion is reached. The mixture is then poured onto the mixture of 1NNaHSO₄ solution and tert-butyl methyl ether (TBME). The phases areseparated, the organic phase is washed with 1N NaHCO₃ solution and theaqueous-alkaline phase is extracted with TBME. The united organic phaseis dried over Na₂SO₄, filtered and the filtrate is evaporated to obtain23.82 g of oil.

Product:

8.) Preparation of Bimatoprost from the Purified Activated Ester

30.9 g of the activated ester according to Example 3. is dissolved in270 ml of THF and to this solution 70 ml of 2M ethylamine dissolved inTHF is added. After the completion of the reaction the mixture is pouredonto the mixture of 1N NaHSO₄ solution and EtOAc. The organic phase iswashed with 1N NaHCO₃ solution. The aqueous-alkaline phase is extractedwith EtOAc. The united organic phase is washed with NaCl solution anddried over Na₂SO₄. The drying material is filtered off and the filtrateis evaporated. To the resulting oil 35 mass % of water is added and theproduct is crystallized. 24.8 g of white bimatoprost crystals of higherthan 99.5% purity are obtained.

Product:

Melting point: 71.9-72.5° C.

HPLC: 99.6% bimatoprost, less than 0.3% trans-bimatoprost, 0.1% otherimpurity

9.) Preparation of Bimatoprost According to Method iii.)

2.00 g of Bimatoprost acid is dissolved in 20 ml of tetrahydrofuran(THF) and at 30° C. first 1.29 g of 2-chloro-1,3-dimethylimidazoliniumchloride (DMC) and 1.44 ml of triethylamine, then after 10 minutes ofstirring 2.57 ml of 2M ethylamine in THF solution are added. Thereaction mixture is gradually, in 1 hour, heated to 70° C. and themixture is stirred at that temperature until the starting materialdisappears (approx. 1 hour). The reaction is followed by TLC.

After the completion of the reaction the mixture is poured onto themixture of 1N NaHSO₄ solution and isopropyl acetate (iPrOAc). Theorganic phase is washed with 1N NaHCO₃ solution, the aqueous-alkalinephase is extracted with iPrOAc. The united organic phase is washed withNaCl solution and dried over Na₂SO₄. The drying material is filtered offand the filtrate is evaporated to obtain 1.41 g of oil.

Product:

10.) Preparation of Crystal Form II. of Bimatoprost from CrudeBimatoprost Oil

To the bimatoprost oil prepared according to Example 6, 35 mass % amountof purified water is added. The mixture is intensively stirred and thendried in vacuum at max. 35° C. temperature, while every 2 hour it isagitated and scratched. After complete dryness the mixture ishomogenized. IR spectrum of this product is shown in FIG. 4 and the DSCcurve of this product is shown in FIG. 6. The X-ray diffraction curve ofproduced Form II is shown in FIG. 8.

Yield: 96.9%

Mp.: 78° C.

DSC onset: 73.56° C.

11.) Preparation of Crystal Form II. of Bimatoprost

The crude bimatoprost prepared according to Example 5. is dissolvedunder heating in 3000-fold amount of diethyl ether. The solvent is thenremoved at (−)20-(−)30° C. by slowly passing through nitrogen gas. Theresulting crystals are homogenized, or first exposed to mechanicaleffect and then homogenized.

Yield: 94.4%

Mp.: 75.9° C.

DSC onset: 72.92° C.

12.) Preparation of Crystal Form II. of Bimatoprost

To the crude bimatoprost prepared according to Example 6, 35 mass %amount of methanol is added. The mixture is intensively stirred and thendried in vacuum at max. 35° C. temperature, while every 2 hour it isagitated and scratched. After complete dryness the mixture ishomogenized.

Yield: 95.8%

Mp.: 77.2° C.

DSC onset: 73.07° C.

13.) Preparation of Crystal Form II of Bimatoprost

To the crude bimatoprost prepared according to Example 6, 17.5 mass %amount of purified water and 17.5 mass % amount of ethanol are added.The mixture is intensively stirred and then dried in vacuum at max. 35°C. temperature, while every 2 hour it is agitated and scratched. Aftercomplete dryness the mixture is homogenized.

Yield: 92.3%

Mp.: 72.9° C.

DSC onset: 72.96° C.

14 a.) Preparation of Bimatoprost Crystal Form I. (According to Example38 of Patent Application US 20090163596)

5.2 g of crude bimatoprost is crystallized from 106 g of acetonitrile:the mixture is heated to a temperature near the boiling point, the hotsolution is cooled to room temperature and the mixture is stirred atthat temperature for 1 hour, then at 0-5° C. for 2 hours. Theprecipitated crystals are filtered off, washed with 20 g of cold (0-5°C.) acetonitrile and dried in vacuum at 0-5° C. for 1 hour, at roomtemperature for half an hour and at 30-40° C. for 2 hours.

4.3 g of crystal form I. of bimatoprost is obtained. Its IR spectrum isshown in FIG. 3, its DSC curve is shown in FIG. 5 and its X-raydiffraction curve of Form I is shown in FIG. 7.

Yield: 83%

Mp.: 62.1° C.

DSC onset: 63.61° C.

b.) Preparation of Bimatoprost Crystal Form II. Started from Form I

To crystal form I. of bimatoprost prepared according to Example 14a, 35mass % amount of purified water is added. The mixture is intensivelystirred and then dried in vacuum at max. 35° C. temperature, while every2 hour it is agitated and scratched. After complete dryness the mixtureis homogenized.

Yield: 97.3%

Mp.: 77.7° C.

DSC onset: 73.14° C.

15.) Preparation of Crystal Form II. of a Mixture of Bimatoprost CrystalForm II. and I

To a 50%-50% mixture of crystal form II. and I. of bimatoprost 35 mass %amount of purified water is added. The mixture is intensively stirredand then dried in vacuum at max. 35° C. temperature, while every 2 hourit is agitated and scratched. After complete dryness the mixture ishomogenized.

Yield: 97.6%

Mp.: 78.2° C.

DSC onset: 73.77° C.

The invention claimed is:
 1. A process for preparing crystal form II ofbimatoprost of formula (IB), comprising:

adding 20-60 mass % protic solvent to a reaction mixture containingbimatoprost, to any crystalline or non-crystalline form of bimatoprost,or to mixtures thereof; stirring and/or scratching the resultingmixture; and drying the resulting mixture; wherein the protic solventcomprises alcohols and/or water; and wherein the alcohols comprisemethanol or ethanol.
 2. The process according to claim 1, wherein dryingis performed in vacuum, at a temperature between 25-50° C.
 3. Theprocess according to claim 1, wherein 35 mass % amount of protic solventis applied.